Experimental autoimmune encephalomyelitis (EAE) is an animal model for human MS that can be induced in experimental animals by immunization with myelin antigens. Both familial aggregation and twin studies in MS and differences in EAE susceptibility in inbred strains of mice suggest a genetic component to these diseases. Genome wide scanning for loci that affect susceptibility to EAE and type 1 diabetes has led to the identification of numerous overlapping loci. Two such loci are Idd3 and Idd5. When compared to NOD mice, NOD.Idd3 congenic are relatively resistant to EAE but when crossed to NOD.Idd5, the NOD.Idd3/Idd5 bi-congenic mice are almost completely resistant to EAE and spontaneous type 1 diabetes. In Idd3, the prime candidate genes are Il2 and Il21, and in Idd5 the main candidates are Ctla4 and Icos. Some of these same genes and pathways have shown linkage in several human autoimmune diseases, thereby supporting the idea that the same genes/pathways may determine susceptibility to autoimmunity in both mouse and man. We hypothesize that the strong epistatic interaction observed between Idd3 and Idd5 is due to the combined action of genetic variants in Idd3 and Idd5 that influence Treg function (Il2 and Ctla4) with those that influence the development of Th17 cells (Il21 and Icos) acting both intrinsically in T cells and extrinsically on antigen presenting cells. To study the interactions between genetic variants within Idd3 and Idd5 and their effect on T cell responses and disease phenotype, we propose to: 1) Examine the impact of Idd3 on T cell development, effector T cell responses and the development of acute and chronic CNS autoimmunity using 1C6 TcR transgenic mice that recognize myelin oligodendrocyte glycoprotein 35-55/IAg7;2) Determine the relative contributions of genetic variants of IL-2 and IL-21 to the effect of Idd3 on effector and regulatory T cell responses by generating novel Idd3 [unreadable]split-haplotype[unreadable] congenics;3) Analyze the molecular basis for epistasis between Idd3 and Idd5 in the development of autoimmune disease by analyzing Idd5 subcongenic strains, generating Idd5 [unreadable]split-haplotype[unreadable] congenics and examining these in combination with Idd3. These studies will identify genes, genetic interactions between two different loci (Idd3 and Idd5) and biological pathways that are involved in mediating susceptibility and resistance to EAE, which may lead to the identification of mechanisms and pathways by which these genes/pathways contribute to inflammation and demyelination in the CNS.